Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Intestinal gluconeogenesis: key signal of central control of energy and glucose homeostasis Gilles Mithieux a,b,c,d , Fabrizio Andreelli e,f,g and Christophe Magnan g,h Introduction The first evidence for the existence of intestinal gluco- neogenesis (IGNG) was published 10 years ago [1–4]. The mechanisms involved in its induction during fasting and experimental diabetes, and their consequences in the redistribution of gluconeogenic substrates to the liver, have been since then further documented [5–8]. It is noteworthy that, over the past 5 years, the existence of this previously unsuspected function of the small intestine has received further accreditation from several groups and from several approaches. Particularly, the expression of the key regulatory genes, that is, glu- cose-6-phosphatase (Glc6Pase) and phosphoenolpyruvate carboxykinase-cytosolic form (PEPCK-C), has been con- firmed in various species, including human [9–12]. In addition, their nutritional regulation has been pointed out [9,10,13], especially during the neonatal period [9,13]. Moreover, tracer-based studies have strongly suggested that IGNG might importantly contribute to endogenous glucose production (EGP) in those situations in which glucose production by the liver is markedly blunted or absent. This includes mice with specific invalidation of PEPCK-C at the liver site, which adapt by enhancing their capacity of glycerol and glutamine gluconeogenesis [14]. Both latter substrates are the main precursors of glucose molecules synthesized by the small intestine [3,4,6,7]. It has also been reported that IGNG might importantly augment the kidney to support EGP, the latter being only decreased by 30%, during the anhepatic phase of liver transplantation in humans [15]. Intestinal gluconeogenesis and central control of food intake It is known from the 1980s that glucose may be a key signaling molecule able to modulate food intake, when it is directly infused into the portal vein. The effects induced might be quantitative, that is, a decreased amount of food ingested [16–18], and also qualitative, that is, a preference for the food associated with the infusion [16]. It has also been suggested, over the same time period, that the delivery of glucose into the portal vein is detected within the walls of the portal vein in a Institut National de la Sante ´ et de la Recherche Me ´ dicale, U855, b Universite ´ de Lyon, Lyon, c Universite ´ Lyon 1, Villeurbanne, d Institut National de la Recherche Agronomique, USC2028, Lyon, e Centre Hospitalier Universitaire, Bichat, f Institut National de la Sante ´ et de la Recherche Me ´ dicale, U695, g Universite ´ Paris 7 and h Centre National de Recherche Scientifique, UMR 7059, Paris, France Correspondence to Gilles Mithieux, UMR INSERM U855, Faculte ´ de Me ´ decine Laennec, rue Guillaume Paradin, 69372 Lyon Cedex 08, France Tel: +33 4 78 77 87 88; fax: +33 4 78 77 87 62; e-mail: mithieux@sante.univ-lyon1.fr Current Opinion in Clinical Nutrition and Metabolic Care 2009, 12:419–423 Purpose of review It has been established that the gut is much more than a digestive tract. It has the capacity to participate in the control of energy homeostasis via the secretion of various hormones. It can also contribute to the control of glucose homeostasis via its high glycolytic capacity and a recently described function, gluconeogenesis. Recent findings In addition to its quantitative role in endogenous glucose production, qualitative roles (i.e. central signaling) were recently described for intestinal gluconeogenesis. In relation to the control of energy homeostasis, intestinal gluconeogenesis, via its detection by a hepatoportal glucose sensor, is able to generate a central signal of control of food intake, resulting in enhanced satiety. This mechanism has been suggested to account for the well known satiety effect initiated by food protein. In relation to the control of glucose homeostasis, intestinal gluconeogenesis has been suggested to be a key factor of the central enhancement of insulin sensitivity for the whole body. It may especially account for the rapid amelioration of the parameters of insulin resistance occurring after gastric bypass, a specific type of surgery of obesity. Summary These new findings on the role of intestinal gluconeogenesis in the central control of energy and glucose homeostasis should be of interest for nutritionists and diabetologists. They pave the way to envision new strategies of prevention or treatment of obesity and type 2 diabetes in humans. Keywords food intake, gluconeogenesis, hypothalamus, insulin sensitivity, intestine Curr Opin Clin Nutr Metab Care 12:419–423 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 1363-1950 1363-1950 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/MCO.0b013e32832c4d6a